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Environmental Pollutants and Metabolic Disorders: The Multi-Exposure Scenario of Life
Brigitte Le Magueresse-Battistoni, Hubert Vidal, Danielle Naville
To cite this version:
Brigitte Le Magueresse-Battistoni, Hubert Vidal, Danielle Naville. Environmental Pollutants and Metabolic Disorders: The Multi-Exposure Scenario of Life. Frontiers in Endocrinology, Frontiers, 2018, 9, pp.582. �10.3389/fendo.2018.00582�. �hal-01885597�
1
Environmental pollutants and metabolic disorders: the multi-exposure scenario of life 1
2 3
Le Magueresse-Battistoni Brigitte, Vidal Hubert, Naville Danielle 4
5 6 7
Affiliations:
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Univ Lyon, CarMeN laboratory, INSERM U1060, INRA U1397, INSA Lyon, Université 9
Claude Bernard Lyon1, 69600 Oullins, France 10
11 12
Corresponding author:
13
Dr. B. Le Magueresse-Battistoni, PhD 14
CarMeN laboratory, INSERM U1060, Faculté de Médecine Lyon-Sud, Chemin du Grand 15
Revoyet, 69600 Oullins, France 16
Phone 33 (0)426235919, Fax 33 (0)426235916 17
E-mail : brigitte.lemagueresse@inserm.fr 18
19 20
Running Title: the cocktail effect of chemicals 21
Key words: cocktail effect; mixture; endocrine disrupting compounds, EDCs; pollutants; sex- 22
dimorphism 23
24 25
2 Abstract
26
Obesity and diabetes have reached epidemic proportions the past few decades and continue to 27
progress worldwide with no clear sign of decline of the epidemic. Obesity is of high concern 28
because it is the main risk factor for a number of non-communicable diseases such as 29
cardiovascular diseases and type 2 diabetes. Metabolic diseases constitute a major challenge 30
as they are associated with an overall reduced quality of life and impose a heavy economic 31
burden on countries. These are multifactorial diseases and it is now recognized that 32
environmental exposure to man-made chemical pollutants is part of the equation. Yet, risk 33
assessment procedures are based on a one-by-one chemical evaluation which does not meet 34
the specificities of the multi-exposure scenario of life, e.g. a combined and long-term 35
exposure to even the smallest amounts of chemicals. Indeed, it is assumed that environmental 36
exposure to chemicals will be negligible based on the low potency of each chemical and that 37
they do not interact. Within this mini-review, strong evidences are brought that exposure to 38
low levels of multiple chemicals especially those shown to interfere with hormonal action, the 39
so-called endocrine disrupting compounds do trigger metabolic disturbances in conditions in 40
which no effect was expected if considering the concentration of each individual chemical in 41
the mixture. This is known as the cocktail effect. It means that risk assessment procedures are 42
not protective enough and thus that it should be revisited for the sake of Public Health.
43 44 45
3 Introduction
46
Obesity and diabetes have reached epidemic proportions the past few decades and continue to 47
progress worldwide with no clear sign of decline of the epidemic in any country. An estimate 48
of 1.9 billion adults were overweight in 2016 of these over 650 million were obese. Children 49
and teenagers are also of high concern with 380 million overweight or obese in 2016. Latest 50
projections by WHO (World Health Organization) indicate that proportion of overweight and 51
obese males and females will continue to increase and reach 3.3 billion by 2030 [1]. Obesity 52
is of high concern because it is the main risk factor for a number of non-communicable 53
diseases such as cardiovascular diseases, certain cancers and type 2 diabetes. Indeed, almost 54
90% of persons suffering from type 2 diabetes are obese and more than 400 million persons 55
will suffer from diabetes by 2030. Metabolic diseases constitute a major challenge as they are 56
associated with an overall reduced quality of life, psychological problems and several 57
physical disabilities [1; 2]. Metabolic diseases also impose a heavy economic burden on 58
countries. It is a major cause of death and it costs an average of $ 2000 billion to the global 59
economy, almost 3 points of GDP (gross domestic product) [3; 4].
60
Metabolic diseases are multifactorial diseases. Apart from genetic susceptibility, life-style risk 61
factors associating over-nutrition and sedentary behavior are major contributors. Yet these 62
causative factors do not explain the magnitude of metabolic diseases or the kinetics of the 63
epidemic. Among other etiologic factors, it is acknowledged that environmental exposure to 64
man-made chemical pollutants is part of the equation, especially those shown to interfere with 65
hormonal action, the so-called endocrine disrupting compounds (EDCs) [5; 6; 7; 8; 9; 10; 11;
66
12].
67
Today’s non-occupational exposure to chemicals is characterized by exposure to tens of 68
thousands of man-made chemicals at low levels. Occupational exposure will not be 69
considered in this mini-review. Another characteristic of non-occupational exposure is its 70
chronicity, from conception onwards thus encompassing gestation and lactation which are 71
periods highly vulnerable to chemicals. It is indeed recognized that threat during the maternal 72
period (e.g. food restriction, chemical stressors) could trigger diseases later in life including 73
metabolic diseases and some cancers, known as the Developmental Origin of Human adult 74
Diseases (DOHaD) concept [13; 14]. In addition, the nature of chemicals and doses to which 75
individuals are exposed may vary across their lifespan. It is also of concern that the number of 76
chemicals to which humans are exposed has continued to grow for more than hundred years 77
4
as is their spatial distribution while the identification of their possible hazardous effects lags 78
behind. Furthermore, exposure is non-deliberate and the exposed population is seldom aware 79
of the nature of the chemicals, the levels to which it is exposed as well as the health 80
consequences. Hence, it appears that risk assessment procedures need to be revisited because 81
the one-by-one evaluation of chemicals does not meet the specificities of the multi-exposure 82
scenario of life.
83
Within this mini-review we aim in presenting basic characteristics on environmental 84
pollutants including EDCs and risk assessment principles operating nowadays. We will next 85
summarize evidences gathered using either natural or artificial mixtures in experimental 86
models, that exposures to low levels of multiple chemicals trigger metabolic disorders in 87
conditions in which no effect was expected if considering the concentration of each individual 88
chemical in the mixture. This is defined as the cocktail effect of pollutants which certainly 89
constitutes one of the biggest health challenges in our modern societies.
90 91
Risk Assessment Evaluation Principles and Limits 92
If industrialization has promoted societal progress improving life expectancy, it also led to the 93
presence of tens of thousands of anthropogenic chemicals transported in the atmosphere and 94
globalizing pollution. Man-made sources of pollution are related to industrial and agricultural 95
activities but also to domestic activities. Pollutants are found in foods, beverages and 96
packaging, clothes, cosmetics and cleaning products, furniture, paints, electronic equipment, 97
plastics and the list is long. Routes of exposure are mostly through diet but also dermal and by 98
inhalation not to mention transfer via placenta, suckling and mouthing behavior placing 99
babies and small infants at particularly high risk for they lack a mature defensive xenobiotic 100
detoxification system. Pollutants differ according to their natural disposal in degradable and 101
low-degradable or persistent pollutants including the lipophilic persistent organic pollutants 102
(POPs) which bio-accumulate through the food chain in fatty tissues with half-lives of several 103
years in humans [15]. Although severely regulated because of environmental toxicity (e.g., 104
the ban of polychlorobiphenyls, PCBs, in the 1970’s), POPs still contaminate air, soil and 105
water compartments. Other pollutants may be more quickly degradable, particularly those 106
produced by the plastic industry (phthalates and bisphenols) but because they are produced at 107
very high volumes and massively found in daily consumables they are consistently detected in 108
human body fluids such as plasma or urine, thus reflecting substantial and continuous 109
5
exposure [16; 17]. However regulatory bodies, e.g., the U.S. Environmental Protection agency 110
(EPA) or the European Food Safety Agency (EFSA), do not consider combined exposures in 111
risk assessment procedures or long-term exposure to even the smallest amount of chemicals.
112
Exposure limits are setup for each individual chemical with the definition of reference doses 113
such as the Tolerable Daily Intake (TDI). TDIs are extrapolated from the no or low observed 114
adverse effect level (NoAEL/LoAEL) in experimental studies assuming linearity of the effects 115
and therefore a threshold under which effects will be negligible. With this assumption (which 116
does not apply to genotoxicant carcinogens for which there is no threshold), it can be deduced 117
that risks arising from environmental exposure to chemicals in a real life exposure scenario 118
will be negligible based on the low potency of each chemical of the mixture. But this 119
assumption excludes several aspects linked to environmental exposure and related to the 120
concept of threshold and the supposed linearity of the adverse effects not to mention the 121
effects at low doses. By low doses it is meant environmental doses or concentrations found in 122
biological fluids or doses approaching toxicological reference values [18]. This indicates that 123
risk assessment procedures may not be protective enough when it comes to environmental 124
exposure to chemicals and more specifically to EDCs.
125 126
EDCs and some of their characteristics 127
EDCs are exogenous substances or mixture of chemicals that interfere with any aspect of 128
hormone action, i.e. EDCs can mimic or antagonize hormonal action and interfere with the 129
mechanism of hormonal production, transport or metabolism [12]. Energy homeostasis is one 130
of the multiple physiological functions controlled by the endocrine system and as such a 131
target of EDCs. It depends on the integrated action of various hormones including insulin, 132
leptin, growth hormone, thyroid hormones, glucocorticoids but also sex hormones.
133
Importantly, the hormonal interplay intricacies and the nature of the hormones at stake vary 134
with age and sex and the state of maturity of the endocrine function of concern. For example, 135
regulation of metabolism is highly age- and sex- dependent e.g. feeding behavior, distribution 136
of fat masses and insulin sensitivity [19]. Thus, considering the intrinsic properties of the 137
endocrine system and the definition of the EDCs based on their mode of action and not their 138
chemical structure, the important parameters that should be considered in risk assessment 139
evaluation are: 1) the dose and the non-linearity of the induced effects, 2) the timing and the 140
length of exposure and 3) the simultaneous presence of several chemicals in mixture [18; 20;
141
21]. Additionally, it is emphasized that the less an endocrine function is mature at the time of 142
chemical exposure, the more dramatic health adverse effects will happen defining highly 143
6
vulnerable periods such as gestation and lactation. For example, ancestral exposure of mice to 144
obesogen chemicals such as organotin tributyltin (TBT) was found to predispose unexposed 145
descendants to obesity [22].
146
About a thousand of chemicals could display EDC activities [23] and a subset was identified 147
as metabolic disruptors because they favor/aggravate obesity and/or insulin resistance leading 148
to diabetes. Metabolic disruptors may include Bisphenol A (BPA) and 149
dichlorodiphenyltrichloroethane (DDT) but also certain pesticides, perfluorinated compounds 150
and phthalates in addition to TBT which can target the signalling pathways of different 151
nuclear receptors including the steroid receptors, but also xenobiotic receptors or receptors 152
activated by peroxisome proliferators, PPAR (peroxisome proliferator-activated receptor) and 153
its heterodimeric partner retinoid X receptor (RXR), not to mention non-genomic signalling 154
pathways and cross-talk with the various nuclear receptors [24; 25; 26; 27].
155 156
Evidences for a cocktail effect from natural or artificial mixtures on metabolic 157
disruption and its sex-dimorphism 158
First evidences of a cocktail effect resulting from exposure to environmental mixtures were 159
brought by scientists invested in Biology of Reproduction with the demonstration of additive 160
effects in mixtures containing chemicals sharing a similar mechanism of action and combined 161
in mixtures at concentrations that individually do not result in observable adverse effects. This 162
was called the something from “nothing” phenomenon demonstrated originally with a mixture 163
of 8 weak estrogenic chemicals [28] but also using combinations of anti-androgens [29] or 164
more complex mixtures of anti-androgenic pesticides, antioxidants, industrial pollutants and 165
chemicals present in personal care products [30]. The concept of additivity was also the basis 166
of the Toxic Equivalent Factor (TEF) set up by the WHO [31] to facilitate risk assessment of 167
“natural” mixtures of dioxins, furans and dioxin-like PCBs, using the dioxin of Seveso 168
(named after the industrial explosion in the village of Seveso, Italy), the most potent in 169
activating the aryl hydrocarbon receptor (AhR), as reference.
170
First demonstrations of mixture effects in the metabolic disruption field area emerged less 171
than 10 years ago (Table 1) when it was observed that rats fed refined salmon oil for 28 days 172
exhibited better metabolic outcomes than rats fed crude salmon oil [32]. These experiments 173
suggested that exposure to POPs commonly present in food chains could trigger enhanced 174
body weight and visceral fat, liver steatosis, glucose intolerance and insulin resistance [32] as 175
well as chronic low-grade inflammation in adipose tissue [33]. A few years later, we brought 176
7
[34] the proof-of-concept study that a mixture of low-dosed pollutants not sharing similar 177
mechanisms of action, could trigger metabolic disturbances in mice. Our original model was 178
designed to take into consideration several parameters of the real life including chronic 179
exposure at low doses covering all developmental stages from the fetal period to adult 180
onwards. It even started when dams were immature females of 5 weeks of age. Both male and 181
female mice (and not only adult males as classically studied) were evaluated to explore the 182
sex-biased mechanisms linked to endocrine disruption. The pollutant cocktail was 183
incorporated in either a high-fat high-sucrose (HFHS) diet [34] or a standard diet [35] to 184
reflect different nutritional situations also considering that food is a primary route of 185
exposure. Thus, we selected pollutants known to contaminate food and not sharing similar 186
mechanisms of action to better reflect a “real” scenario of exposure. The mixture was made of 187
two persistent pollutants including the most powerful dioxin (2,3,7,8-Tetrachlorodibenzo-p- 188
dioxin, TCDD) and the most abundant of the non-dioxin like PCBs (PCB153). The other two 189
were short-lived pollutants including BPA, one of the substances most investigated for its 190
endocrine disrupting activities [18; 36; 37] and the di-[2-ethylhexyl] phthalate (DEHP) largely 191
used to soften plastics. Each chemical in the mixture was used at a dose in the range of its 192
tolerable daily intake (TDI). With regards to their modes of action, these well-recognized 193
EDCs display mostly estrogeno-mimetic and anti-androgenic activities for BPA and DEHP, 194
respectively; while dioxins interact with AhR and non-dioxin like PCBs may interact with 195
other xenobiotic receptors such as constitutive androstane receptor (CAR) and pregnane X 196
receptor (PXR) [18; 24; 38; 39]. Moreover, interaction of pollutants of the mixture may also 197
occur with other receptors like thyroid receptors or glucocorticoid receptors not to mention 198
extensive cross-talks which may occur via direct or indirect interaction with metabolic 199
pathways regulating energy homeostasis as reviewed elsewhere [8; 24]. With such a model, 200
we originally demonstrated that the metabolic adverse impact in mice exposed to the mixture 201
lifelong occurs in the absence of any weight gain but was strongly sex-dependent [34; 40], 202
and also related to the age of the animals [41] and their nutritional environment [35]. The 203
female offspring exposed to the mixture incorporated in a HFHS diet exhibited aggravated 204
glucose intolerance, impaired estrogen signalling in liver and enhanced expression of 205
inflammatory markers in the adipose tissue at adulthood as compared to non-exposed females.
206
This suggested that pollutants could lessen the protection of estrogens against the 207
development of metabolic diseases. Importantly, these effects were not observed in younger 208
females or in males which are characterized by different hormonal milieu in line with 209
endocrine disrupting effects. Males had impaired cholesterol metabolism resulting from 210
8
enhancement of genes encoding proteins related to cholesterol synthesis and degradation in 211
bile salts when fed a HFHS diet containing the mixture of pollutants [34; 41]. The observed 212
metabolic impact in females was dependent on the nutritional context as female mice fed a 213
standard diet and exposed similarly to the mixture showed alteration of lipid homeostasis with 214
no difference in body weight or glucose tolerance [35]. Importantly, pollutants elicited 215
distinct and common features as compared to a HFHS diet as revealed by a comparative 216
hepatic transcriptomic study. Among features resulting from pollutant exposure in the liver 217
was the finding of several dysregulated genes belonging to the circadian clock metabolic 218
pathway including major canonical genes of the core clock (Period circadian regulators 1-3, 219
Arntl1 encoding BMAL1 and Clock) and clock regulators thus highlighting circadian 220
disruption [35]. None of the described effects observed in females were described in males 221
pointing to the sex-dimorphic impact of pollutants consistent with the sex-dimorphic 222
regulation of energy homeostasis [42] (Table 1).
223
Other combinations of low-dosed pollutants in mixture have later been tested in mouse [43;
224
44; 45] or rat [46] models as well as in juvenile seabream [47]. These studies also reported 225
significant alterations of the hepatic gene signature consistent with the liver being the primary 226
site for detoxification (Table 1). Interestingly, whenever males and females have been studied, 227
sex-differences have also been observed [43; 45; 46] as compiled (Table 1) which highlights 228
the necessity, as mandated by the National Institutes of Health (NIH), to consider sex as a 229
biological variable [48]. Also consistent with our data [34] [35], it was shown that the 230
nutritional component was as well a variable to consider. Indeed, exposure to a mixture of 231
POPs [44], to dioxins [49] or to a pharmaceutical drug cocktail [50] resulted in differential 232
metabolic responses between lean and obese mice. Outcomes surveyed included hepatic 233
steatosis and systemic lipid metabolism [44], hyperglycaemia and hepatic mitochondrial 234
function [50] and hepatic fibrosis [49]. Whether this is linked to substantial alterations of the 235
expression of hepatic xenobiotic processed genes [35; 51], resulting in differential ability of 236
the liver to detoxify chemicals, warrants further studies.
237 238
Conclusions 239
The current legislation on chemical risk assessment is definitely obsolete and needs to be 240
updated to take into account the cocktail effect of mixtures. This is certainly a major 241
challenge for the near future as environmental pollutants are risk factors for numerous 242
pathologies also including cancers and hormono-dependent cancers among them, for which 243
9
obesity is a risk factor [7]. Importantly, it was assumed that the carcinogenic potential of 244
chemical mixtures may be more important than that of individual carcinogens in the real 245
world [52]. It will also be critical to enhance our knowledge on chemical toxicity as according 246
to the US EPA, it is available for less than 20% of substances produced at significant 247
amounts, worldwide [53]. While additivity was demonstrated for mixture of low-dosed 248
chemicals affecting similar outcomes [54], when it comes to mixtures with molecules acting 249
differently, which better fits the real life scenario, the problem becomes more complex 250
because chemical actions may [46; 55] or may not be independent. For example, in an in vitro 251
model of mesenchymal cells, BPA, DEHP and TBT could not be deduced from single 252
compound experiments [56]. As well synergistic activation of human PXR was observed in an 253
in vitro model of hepatocytes (HepG2) by binary cocktails of pharmaceutical and 254
environmental compounds [57]. Another limitation to the additivity concept of cocktail effect 255
lies in the fact that a pollutant can alter the metabolism of another pollutant present in the 256
mixture and potentially its bioavailability [58]. Moreover, some products may, by modifying 257
the epigenome, leave an imprint on unexposed generations as recently demonstrated with 258
TBT on RXR activation [59].
259
The problem posed by the cocktail effect is a virtually insurmountable challenge but it will 260
have to be overcome for the sake of public health. Political authorities should work to reduce 261
the exponential production of industrial chemicals. In addition, integrative approaches 262
combining knowledge gathered in epidemiologic and biomonitoring studies, but also 263
experimental, in vitro and in silico studies, together with computational approaches to 264
construct predictive models, will certainly help at moving a path forward.
265 266
Conflict of Interest Statement 267
The authors declare that the research was conducted in the absence of any commercial or 268
financial relationship that could be construed as a potential conflict of interest.
269 270
Funding 271
This work was supported by INSERM and University of Lyon1 to INSERM U1060 272
273
Author Contributions 274
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The manuscript was written by BLMB. DN created the Table and participated in the editing 275
of the manuscript. HV participated in the editing of the manuscript. All authors approved the 276
final version of the manuscript.
277 278
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14
Table 1: Metabolic effects of pollutants in mixture and sex-dimorphism 466
Mixture of pollutants
Composition Animal
Model
Metabolic effects of the mixture
References
Natural mixture:
crude or refined salmon oil in high-
fat (HF) diet
mixture of Persistent Organic Pollutants (POPs): organochloride
pesticide,
Dichlorodiphenyltrichloroéthane (DDTs), dioxins,
Polychlorobiphenyls (PCBs)
Adult male Sprague- Dawley rat (28 days of exposure)
HF+ crude oil vs HF:
insulin resistance, abdominal obesity, liver
steatosis, down- regulation of genes
involved in lipid homeostasis (Insig-1 and
Lipin 1) in liver
Ruzzin et al, 2010 [32]
Very high fat diet (VHF) or Western
diet (WD) containing farmed
salmon fillet (VHF/S and WD/S)
mixture of Persistent Organic Pollutants (POPs): organochloride
pesticides, dioxins, furans and Polychlorobiphenyls (PCBs)
8-week old male C57BL/6J
mice (8 weeks exposure for
VHF; 6 weeks for
WD)
VHF/S vs VHF:
aggravation of insulin resistance, visceral obesity and glucose intolerance, adipose tissue inflammation.
Increased blood glucose and plasma insulin.
WD/S vs WD: enhanced body weight, overgrowth
of adipose tissue, increased glucose intolerance and insulin resistance with increased
plasma insulin
Ibrahim et al, 2011 [33]
Combination of four Endocrine
Disrupting Chemicals (EDCs) in high fat-high sucrose
(HFHS) diet
2,3,7,8-Tetrachlorodibenzo-p- dioxin (TCDD),
Polychlorobiphenyls (PCB) 153, Bisphenol A (BPA), di (2- ethylhexyl) phthalate (DEHP)
each at reference doses (Tolerable Daily Intake, TDI for
Human)
Male and female C57Bl/6J
mouse (exposure from pre- conception, gestation to 12 weeks
of life)
Sex-dependent metabolic disorders in the absence of weight gain. In males,
increased hepatic expression of genes encoding proteins related
to cholesterol biosynthesis associated
with a decrease in hepatic total cholesterol
levels. In females, marked deterioration of
glucose tolerance associated with decreased expression of
gene encoding ERα as well as estrogen target genes and increased
expression of gene encoding the estrogen
sulfotransferase SULT1E1.
Naville et al, 2013
[34]
15 Combination of
Endocrine Disrupting Chemicals (EDCs)
administered intragastrically to
the exposed group.
Combination of di (2-ethylhexyl) phthalate, DEHP (15mg/kg bw)
with a mixture of Polychlorobiphenyls, PCBs (Aroclor 1254 at 7.5mg/Kg bw/day)
female and male mice (12 days of
exposure)
Increased liver weight but no difference in body
weight; in liver, increased expression of
gene encoding Peroxisome Proliferator-
Activated Receptor (PPAR) (males and
females), decreased expression of genes encoding Estrogen Receptor (ER)α and phospholipase A (PLA)
only in males
Lin et al, 2015
[43]
Different combinations of 3 pollutants (2 by 2
or all 3)
Nonylphenol (NP), tert- octylphenol (t-OP), Bisphenol A (BPA) (5mg/kg bw/day of each)
Juvenile seabream (21 days)
Hepatic steatosis, modulation of the expression of genes
involved in lipid metabolism (ppars, lpl,
fasn, hsl) mostly using NP+t-OP or BPA+NP.
Effects milder than those obtained with
one chemical (hypothesis of possible
interactions among compounds).
Carnevali et al, 2017
[47]
Combination of four Endocrine
Disrupting Chemicals (EDCs)
in low fat diet
2,3,7,8-Tetrachlorodibenzo-p- dioxin (TCDD),
Polychlorobiphenyls (PCB) 153, Bisphenol A (BPA), di (2- ethylhexyl) phthalate (DEHP)
each at reference doses (Tolerable Daily Intake, TDI for
Human)
female C57Bl6/J
mouse (exposure from pre- conception, gestation to 12 weeks
of life)
Alteration of lipid homeostasis (increase
of hepatic triglycerides) with no
difference in body weight or glucose
tolerance.
Transcriptome analysis in liver highlights dysregulation of genes
involved in fatty acid/lipid and circadian clock metabolic pathway.
Most of these effects were observed in females and not in
males.
Labaronne et al, 2017
[35]
16 Mixture of five
prevalent organochlorine pesticides or their metabolites and five Polychlorobiphenyls (PCBs) present in
contaminated salmon [32]
Dichlorodiphenyldichloroethylene(
p,p'DDE);
Dichlorodiphenyldichloroéthane (p,p'DDD); hexachlorobenzene, dieldrin, trans-nonachlor, PCB- 153, PCB-138, PCB-118, PCB-77,
PCB-126 (oral gavage twice weekly during 7 weeks)
5 week-old male wild
type C57Bl/6J and male ob/ob mice
Alteration of systemic lipid metabolism in ob/ob mice: increased
hepatic triglycerides (TG) with decrease of
serum TG levels (no difference either in
plasma glucose or insulin levels or in inflammation in liver or
adipose tissue).
Induction of the expression of Cyp3a11 in WT mice not in ob/ob
mice
Mulligan et al, 2017
[44]
Mixture of 13 chemicals
Carbaryl, dimethoate, glyphosate, methomyl, methyl parathion, triadimefon, aspartame, sodium
benzoate,
Ethylenediaminetetraacetic acid (EDTA), ethylparaben, butylparaben, BPA, acacia gum (6-
month exposure in drinking water at three different doses: low,
medium and high).
8-week old Female and
Male Sprague- Dawley rats
Increased body weight and alteration of hepatotoxic parameters (increased level of total
bilirubin, alanine aminotransferase and alkaline phosphatase) even at low dose and only in males. Increased catalase activity with the low doses both in males
and females. Also evidence for sex differences in some markers of the redox status (catalase levels,
protein carbonyls).
Docea et al, 2018
[60]
Mixture of 4 fungicides and 2
insecticides in standard diet
Ziram; Chlorpyrifos; Thiacloprid;
Boscalid; Thiofanate; Captan (52 weeks of exposure; at Tolerable Daily Intake, TDI for Humans)
16-week-old female and
male C57BL/6J
(WT) and Constitutive
Androstane Receptor
(CAR)- invalidated
mice
In Wild Type (WT) males: increased body weight (not seen in male
CAR-/-) and adiposity, hepatic steatosis, fasting
hyperglycemia and strong glucose
intolerance.
In WT females: fasting hyperglycemia and slight
glucose intolerance.
Pesticide-exposed CAR- /- females exhibited pesticide toxicity with increased body weight
and mortality rate.
Sexually dimorphic alterations of various
metabolic pathways
Lukowicz et al, 2018
[45]
17 Pesticide mixture
containing six chemicals at 3 different doses (noted 5%-16%-
37.5%)
Cyromazine, MCPB (4-(4-chloro- 2-methylphenoxy) butanoic acid), Pirimicarb, Quinoclamine, Thiram,
Ziram (daily oral gavage of pregnant rats from gestation day 7
to pup day 16)
Wistar rats - Male and
Female offspring studied until 15 weeks of
life
Decreased body weight at birth for both sexes with the highest dose.
No difference in body weight after 15 weeks.
Differences observed between males and females for several regulatory factors (such
as leptin).
Svingen et al, 2018
[46]
467 468
