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What can genes tell us about children's toxicity risk?

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A number of chronic health concerns seen in children are linked to toxicity and resultant oxidative stress, enzyme dysfunction and inflammation. Some examples of these conditions include allergies and chemical sensitivities, immune dysfunction, neurological and behavioural conditions, and cardio-metabolic diseases.

Toxicities may develop due to overexposure or deficiencies in the nutrients required to support detoxification and protect against heavy metal uptake (e.g. zinc deficiency increases the risk of copper overload), for example. Another aetiologic factor can be genetic susceptibility, whereby the presence of certain single nucleotide polymorphisms (SNPs) render a child more susceptible to toxic overwhelm and subsequent symptoms.

SNPs and toxicity risk

Certain SNPs may turn-up or turn-down the functioning of phase 1 detoxification enzymes. When phase 1 pathways are turned-down, accumulation of un-metabolised toxins can occur.

Alternatively, in circumstances where SNPs and other factors (e.g. toxin exposure) are turning phase 1 enzyme activity up, toxicity symptoms may also occur. This is due to many of the metabolites from phase 1 being more reactive than they were to begin with. These reactive metabolites require deactivation by phase 2 conjugation to make them water-soluble, inert and ready to be excreted. If phase 2 is unable to keep up with the demand of a rapid-paced phase 1, the result can be an uncoupling of the phases and subsequent increase in these reactive metabolites that are known to cause damage.

Further contributing to this uncoupling is not only an insufficiency of the substrates required for the heavily nutrient-dependant pathways of phase 2 (e.g. glutathionation, methylation, acetylation, sulphation, glucuronidation), but also the presence of SNPs which turn-down the enzymes that catalyse these phase 2 reactions. If we add to this SNPs that impact the functioning of endogenous antioxidants, then we can see that the body is less able to protect itself from the negative impact of the oxidative stress created when uncoupling occurs and when un-metabolised toxins accumulate. Therefore, to understand more about a patient’s genetic susceptibility to toxicity, looking at SNPs present on genes which code for phase 1, phase 2 and endogenous antioxidant enzymes may be useful.

The research connecting SNPs and childhood conditions is in its infancy. We still need to understand more about how multiple SNPs may interact with each other and certain environmental exposures. However, we do know:

  • SNPs within glutathione S-transferase genes (GSTP1) are linked to an increased risk of asthma triggered by air pollution from traffic.[1]
     
  • GSTP1 and paraoxonase (PON1) SNPs (amongst others) are suggested to have an association with autism risk.[2]
     
  • Children with N-actetyltransferase (NAT2) SNPs,which result in “slow” acetylators, have a predisposition to atopy.[3]

Conducting DNA testing which identifies SNPs that impact detoxification and antioxidant function may add to the patient picture. It may help to identify specific toxins that are best avoided more strictly as well as what interventions may be most appropriate.

A closer look at specific SNPs

Phase 1 enzymes
The phase 1 enzymes include the cytochrome P450 (CYP) enzymes. Looking at each of these can determine a number of things. SNPs which turn a CYP enzyme down would suggest that a patient may need to pay particular attention to avoid the toxins worked on by that enzyme to prevent accumulation. SNPs which turn a CYP enzyme up would also suggest that the toxins metabolised by that enzyme should be avoided. The reason is that exposure to those toxins would result in rapid conversion to potentially harmful metabolites that may cause damage (especially if phase 2 is not working well or antioxidant status isn’t good). In both circumstances, supporting antioxidant status and healthy phase 2 and excretion pathways is essential.

Examples of phase 1 genes
The genes below code for enzymes of the same name.

  • CYP1B1 Metabolises oestrogens to reactive 4-hydroxy metabolites, as well as breaking down environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), which are released from substances such as cigarette smoke, car exhaust fumes and chargrilled meats. A SNP can increase activity, leading to higher harmful oestrogens and other reactive metabolites that cause DNA damage.
     
  • CYP1A1 Metabolises oestrogens into the 2-hydroxy metabolites. Genetic variations that increase enzyme activity may increase the amount of 2OH oestrogen metabolites as well as potentially toxic and reactive metabolites from environmental pollutants.
     
  • CYP2A6 Involved in the oxidation of tobacco, herbicides, pollutants and xenobiotics. In addition, CYP2A6 is the only enzyme that is able to metabolise coumarin. Coumarin is found naturally in many plants, but high levels have been detected in tonka beans, certain forms of cinnamon and potentially some plants used for herbal medicine. A known SNP reduces enzyme activity, making patients slow or poor metabolisers of nicotine and coumarin, and thus potentially more susceptible to negative toxic effects.
     
  • CYP2D6 Involved in the metabolism of over 25% of all clinically used medicines. Common examples include opioids, beta-blockers, antidepressants, anti-psychotics and tamoxifen. CYP2D6 is also involved in the synthesis of dopamine and serotonin. A known SNP can result in reduced enzyme activity and loss of function. Patients may have an increased susceptibility to drug toxicity at standard doses.

Examples of phase 2 and antioxidant genes

  • GSTP1 codes for the enzyme glutathione S-transferase P1. This is a phase 2 detoxification enzyme that conjugates glutathione to reactive metabolites and xenobiotics, converting them to less reactive substances in order to be excreted from the body. Unlike other GSTs that are mainly expressed in the liver, GSTP1 is predominantly expressed in the lungs, brain, breast and placenta.

    A SNP within this gene can reduce enzyme activity and increases the risk of toxicity and oxidative stress. Some examples of toxins metabolised by glutathione include heavy metals (e.g. aluminium, copper, lead and cadmium), harmful oestrogen metabolites, and pesticides.

    If this SNP is present it can be useful to optimise glutathione status (consider also SNPs on the CBS gene that turn-down its function, as this can lead to reduced levels of glutathione and homocysteine accumulation). Exposure to toxins requiring glutathione for removal can also deplete status. For example, aluminium exposure (e.g. through antacid use) is shown to deplete glutathione.

    Supplemental glutathione may be useful, while certain natural compounds are known to help stimulate GSTP1 release (e.g. St Mary’s thistle, curcumin, ginger, quercetin). In addition, using ingredients that help enhance Nrf2 expression can help to turn-on GSTP1 release (e.g. EGCG from green tea, curcumin, selenium, resveratrol).
     

  • MTHFR codes for the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme that reduces 5,10-methylenetetrahydrofolate (5,10-MTHF) to produce 5-methyltetrahydrofolate (5-MTHF). 5-MTHF is the form of folate that can give a methyl group to homocysteine to make methionine that is then used to synthesise s-adenosylmethionine (SAMe). SAMe is a key methyl donor in the body and methylation with SAMe is an important part in detoxification of endogenous and exogenous toxins.

    SNPs within the MTHFR gene can reduce the enzyme’s function, resulting in potentially higher homocysteine, lower methionine and SAMe. Potential harm from this may be increased where there are other SNPs that impact the methionine-homocysteine cycle (e.g. MTHFR, MTR, CBS, TCN2, FUT2, BHMT) and where there are SNPs that turn down methyltransferase enzymes that require SAMe (e.g. COMT) to metabolise compounds, and where toxic homocysteine metabolites aren’t broken down efficiently (e.g. PON1).

    These patients may benefit from biologically active forms of folate (e.g. MTHF or folinic acid), SAMe supplementation, vitamin B6, vitamin B2 and a diet rich in natural folates (e.g. green vegetables).

  • NAT2 codes for the N-acetyltransferase 2 enzyme. This is involved in phase 2 detoxification and catalyses the acetylation of various chemicals present in the diet (e.g. polycyclic aromatic amines (PAAs), polychlorinated biphenyls (PCBs)), environmental and pharmaceuticals medications.

    SNPs can increase or decrease activity of this enzyme. Individuals who are slow acetylators may be more chemically sensitive because reduced NAT2 enzyme activity may prolong the action of chemicals and pharmaceutical medications, thus enhancing toxicity. Slow acetylation has been associated with increased risk for oxidative stress, DNA damage and may play a role in conditions such as endometriosis.

    It is important to note that rapid acetylators can add acetyl groups so quickly that mistakes may occur, resulting in some toxins becoming more reactive; this is of particular concern when exposed to a high toxic load. Therefore, any SNP on this gene should be considered as a contributor to increased toxicity risk. Nutrients that support acetylation include vitamin B5, vitamin C and certain short chain fatty acids (SCFAs) produced by probiotic bacteria.

  • PON1 codes for paraoxonase 1. This is a calcium-dependent enzyme that breaks down a variety of compounds, including organophosphates (e.g. glyphosate), glucuronide drugs, cyclic carbamates (e.g. pesticides), thiolactones (e.g. homocysteine thiolactone) and oestrogen esters. PON1 works to help prevent low-density lipoprotein (LDL) oxidation and also breaks down homocysteine-thiolactone, helping to reduce homocysteine mediated oxidative stress and protein damage.

    Patients with a SNP that turns-down PON1 function may be at greater risk of cardiovascular disease, but also the negative effects of pesticides and high homocysteine.
    Thus, consider folate, vitamin B6 and B12 status (due to their deficiency being linked to high homocysteine), plus other SNPs which may contribute to homocysteine elevation (e.g. MTHFR, MTR, CBS (SNPs that turn-down CBS specifically), TCN2, FUT2, BHMT).

    Eating organically may be particularly useful for patients with this SNP, in order to reduce pesticide exposure, and avoid insect sprays and cockroach baits etc. in the home. PON1 activity is shown to be increased after supplementing with vitamin C, vitamin E, folate, carotenoids, mono and polyunsaturated fatty acids, selenium and polyphenols.

  • CAT, GPX1, SOD2 code for the enzymes catalase (CAT), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (SOD), respectively. These are some of the body’s key endogenous antioxidants that work to protect it against oxidative stress, such as that caused by toxicity. As a result, SNPs within these genes that compromise functioning may require attention and consideration.

    For example, GPX1 is dependent on selenium and reduced glutathione (GSH) availability, whilst SOD is dependent on manganese. Expression of the transcription factor Nrf2 is involved in triggering the release of these protective enzymes. Consequently, supporting Nrf2 expression can assist in optimising antioxidant enzyme availability.
    Additional genes that directly or indirectly influence antioxidant status include:
       •    NQO1: reduces reactive and harmful quinones, while also converting ubiquinone to ubiquinol
       •    BCMO1: involved in converting carotenoids to vitamin A
       •    SLC23A1: involved in regulation of vitamin C
       •    CBS: involved in converting homocysteine to cystathione, the precursor for cysteine and glutathione synthesis (two antioxidants that also support detoxification). This is dependent on vitamin B6.

Suggested pathology

  • Intestinal permeability assessment (urine)
  • Homocysteine (blood) - may give an indication of how well the methionine/homocysteine cycle
  • and transsulphuration pathway are functioning
  • Organic acids test - to assess for factors such as dysbiosis, nutrient levels and oxidative stress
  • Copper:zinc ratio (blood)
  • Liver function test (blood)
  • Heavy metal analysis

Suggested treatments

  • Identify sources of specific toxins to which an individual has sensitivities:
  • Diet
      -  fish consumption
      -  meat, avoid charring
      -  personal care products (read labels of toothpaste, shower gels)
      -  canned food consumption
      -  plastics (ensure the use of BPA-free plastics for storage)
      -  consider organic eating is possible (at least for specific foods)
  • Cigarette smoke exposure
  • Insect sprays, pest treatment in the home
  • Wash new clothes and bedsheets prior to initial use
  • Consider current medications (e.g. antacid use) and look at medication history (e.g. antibiotic use)
  • Gut healing and soothing with glutamine, mastic gum, curcumin and slippery elm to support detoxification and elimination (look for powdered options)
  • Liposomal glutathione to support detoxification and antioxidant status (or powdered n-acetylcysteine (NAC) if easier to administer)
  • Nrf2 support with ingredients such as resveratrol, EGCG from green tea, selenium and curcumin. For children specifically look for selenium in drop form and curcumin capsules that can be broken open
  • Milk thistle to support stimulation of detoxification enzymes such as GSTP1 (look for suitable powdered option)
  • Consider if anxiety is a concern and support with zinc (try liquid form) and powdered magnesium with B vitamins. Powdered versions of GABA or L-theanine may also be considered (chronic anxiety can compromise healthy detoxification)
  • Probiotic and prebiotic powders to support detoxification and excretion
  • 1.5-2L of water daily to support elimination
  • B vitamins if required to support phase 2 pathways
    of methylation, glycination and acetylation
  • Zinc and selenium to assist in protecting against excess heavy metal uptake (look for both nutrients in liquid form for ease of use with children)

In summary, genetic variations can influence a child’s risk of toxicity-related conditions. Variations may exist within genes that code for phase 1 and phase 2 detoxification enzymes, as well as genes that influence a child’s antioxidant capacity and ability to protect themselves against the effects of toxic burden. As a result, DNA testing may assist in providing additional insight ad possible direction when designing
a treatment protocol.

Examples of potentially toxic substances and common sources of exposure

Organophosphates
Pesticides/insecticides and herbicides e.g. glyphosate
Cyclic carbamates
Pesticides/insecticides, some cosmetic preservatives and drugs
Parabens
Often used as a preservative in cosmetics, toothpaste, shower gel, moisturiser, fake tan, personal lubricants
and pharmaceuticals
Polycyclic aromatic amines (PAAs)
Charred meat, car exhaust fumes and cigarette smoke
Polycyclic aromatic hydrocarbons (PAH)
Charred meat, car exhaust fumes and cigarette smoke
Aluminium
Antiperspirant deodorant, antacids, cooking acidic food
in aluminium cookware
Bisphenol-A (BPA)
Certain plastics, point of sale receipts, lining inside food cans
Polychlorinated biphenol (PCB)
Contaminated fish
Polybrominated diphenyl ethers (PBDEs)
Flame retardants used in computers, carpet, furniture fabrics and mattresses
Thiolactone
Homocysteine produced endogenously
Benzene
Tobacco smoke, automobile service stations, exhaust
from motor vehicles and industrial emissions
Phthalates
Hard plastics, including those used in water and soda bottles, and recycled PVC.

References

  1. MacIntyre EA, Brauer M, Melén E, et al. GSTP1 and TNF Gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) study. Environ Health Perspect 2014;122(4): 418-424. [Abstract]
     
  2. Rossignol DA, Genuis SJ, Frye RE. Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry 2014;4:e360. [Abstract]
     
  3. Zielińska E, Niewiarowski W, Bodalski J, et al. Arylamine N-acetyltransferase (NAT2) gene mutations in children with allergic diseases. Clin Pharmacol Ther 1997;62(6):635-642. [Abstract]

 


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belinda_reynolds's picture
Belinda Reynolds

Belinda is a dietitian and Senior Educator at one of Australia's leading nutraceutical companies. She graduated with an Honours Degree in Nutrition and Dietetics, and has been involved in the complementary medicine industry for over 15 years. Her key interests are immune modulation, the human microbiome and the impact they have on overall health.